Method of administration of gamma hydroxybutyrate with monocarboxylate transporters

ABSTRACT

One embodiment of the present invention is to improve the safety and efficacy of the administration of GHB or a salt thereof to a patient. It has been discovered that the concomitant administration of an MCT inhibitor, such as diclofenac, valproate, or ibuprofen, will affect GHB administration. For example, it has been discovered that diclofenac lowers the effect of GHB in the body, thereby potentially causing an unsafe condition. Furthermore, it has been discovered that valproate increases the effect of GHB on the body, thereby potentially causing an unsafe condition.

This application is a continuation application of U.S. patentapplication Ser. No. 13/837,714, filed Mar. 15, 2013, which claims thebenefit of U.S. Provisional Application No. 61/771,557, filed Mar. 1,2013, and U.S. Provisional Application No. 61/777,873, filed Mar. 12,2013, all of which applications are hereby incorporated by reference intheir entireties.

BACKGROUND

This application relates to methods for safely administering gammahydroxybutyrate (GHB) together with one or more other monocarboxylatetransporter (MCT) inhibitors for therapeutic purposes. Exampletransporter inhibitors are valproate, diclofenac, and ibuprofen andcombinations thereof.

SUMMARY OF THE INVENTION

One embodiment of the present invention is a method for treating apatient who is suffering from excessive daytime sleepiness, cataplexy,sleep paralysis, apnea, narcolepsy sleep time disturbances, hypnagogichallucinations, sleep arousal, insomnia, and nocturnal myoclonus withgamma-hydroxybutyrate (GHB) or a salt thereof, comprising: orallyadministering to the patient in need of treatment, an adjusted dosageamount of the salt of GHB when the patient is receiving a concomitantadministration of valproate. In certain embodiments, the adjusted amountis reduced at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, or 50% of the normal dose of the salt of GHB normally given to thepatient. In certain embodiments, the amount of GHB is reduced at leastabout 10% and about 30% of the normal administration and the dailyadministration of the GHB salt is between 1 gram and 10 grams. Incertain embodiments, the adjusted amount is reduced between the rangesof about 1% to 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%,about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%,about 40% to 45%, or about 45% or 50%, relative to the normal dose ofthe salt of GHB normally given to the patient. In certain embodiments,the adjusted amount is reduced between the range of about 1% to 50%,about 1% to 45%, about 1% to 40%, about 1% to 35%, about 1% to 30%,about 1% to 25%, about 1% to 20%, about 1% to 15%, about 1% to 10%,about 1% to 5%, about 5% to 50%, about 5% to 45%, about 5% to 40%, about5% to 35%, about 5% to 30%, about 5% to 25%, about 5% to 20%, about 5%to 15%, about 5% to 10%, about 10% to 50%, about 10% to 45%, about 10%to 40%, about 10% to 35%, about 10% to 30%, about 10% to 25%, about 10%to 20%, about 10% to 15%, about 15% to 50%, about 15% to 45%, about 15%to 40%, about 15% to 35%, about 15% to 30%, about 15% to 25%, about 15%to 20%, about 15% to 15%, about 15% to 10%, about 20% to 50%, about 20%to 45%, about 20% to 40%, about 20% to 35%, about 20% to 30%, about 20%to 25%, about 25% to 50%, about 25% to 45%, about 25% to 40%, about 25%to 35%, about 25% to 30%, about 30% to 50%, about 30% to 45%, about 30%to 40%, about 30% to 35%, about 35% to 50%, about 35% to 45%, about 35%to 40%, about 40% to 50%, relative to the normal dose of the salt of GHBnormally given to the patient.

Another embodiment of the invention is a method of safely administeringGHB a salt thereof for excessive daytime sleepiness, cataplexy, sleepparalysis, apnea, narcolepsy, sleep time disturbances, hypnagogichallucinations, sleep arousal, insomnia, and nocturnal myoclonus in ahuman patient, comprising: determining if the patient is has taken, orwill take a concomitant dose of valproate; orally administering areduced amount of the GHB or GHB salt to the patient compared to thenormal dose so as to diminish the additive effects of the GHB or GHBsalt when administered with valproate. The amount of GHB is reduced atleast 10% to 30%, or at least +15% of the normal administration.

One embodiment of the present invention is a method for treating apatient who is suffering from excessive daytime sleepiness, cataplexy,sleep paralysis, apnea, narcolepsy sleep time disturbances, hypnagogichallucinations, sleep arousal, insomnia, and nocturnal myoclonus withGHB or a salt thereof, comprising: orally administering to the patientin need of treatment, an adjusted dosage amount of the salt of GHB whenthe patient is receiving a concomitant administration of diclofenac. Incertain embodiments, the adjusted amount is at least about 1%, 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% higher than the normal dose ofthe salt of GHB normally given to the patient. In certain embodiments,the increased amount of GHB is at least about 15% more than the normaladministration and the daily administration of the GHB salt is between 1gram and 10 grams. In certain embodiments, the adjusted amount isincreased between the range of about 1% to 5%, about 5% to 10%, about10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about30% to 35%, about 35% to 40%, about 40% to 45%, or about 45% or 50%,relative to the normal dose of the salt of GHB normally given to thepatient. In certain embodiments, the adjusted amount is increasedbetween the range of about 1% to 50%, about 1% to 45%, about 1% to 40%,about 1% to 35%, about 1% to 30%, about 1% to 25%, about 1% to 20%,about 1% to 15%, about 1% to 10%, about 1% to 5%, about 5% to 50%, about5% to 45%, about 5% to 40%, about 5% to 35%, about 5% to 30%, about 5%to 25%, about 5% to 20%, about 5% to 15%, about 5% to 10%, about 10% to50%, about 10% to 45%, about 10% to 40%, about 10% to 35%, about 10% to30%, about 10% to 25%, about 10% to 20%, about 10% to 15%, about 15% to50%, about 15% to 45%, about 15% to 40%, about 15% to 35%, about 15% to30%, about 15% to 25%, about 15% to 20%, about 15% to 15%, about 15% to10%, about 20% to 50%, about 20% to 45%, about 20% to 40%, about 20% to35%, about 20% to 30%, about 20% to 25%, about 25% to 50%, about 25% to45%, about 25% to 40%, about 25% to 35%, about 25% to 30%, about 30% to50%, about 30% to 45%, about 30% to 40%, about 30% to 35%, about 35% to50%, about 35% to 45%, about 35% to 40%, about 40% to 50%, relative tothe normal dose of the salt of GHB normally given to the patient. Seethe product insert for normal dose ranges of GHB as sold by JazzPharmaceuticals. GHB is commercially known as Xyrem®.

In another embodiment, the invention is a method of safely administeringa GHB salt for excessive daytime sleepiness, cataplexy, sleep paralysis,apnea, narcolepsy, sleep time disturbances, hypnagogic hallucinations,sleep arousal, insomnia, and nocturnal myoclonus in a human patient,comprising: determining if the patient has taken, or will take aconcomitant dose of diclofenac; orally administering an increased amountof a GHB salt to the patient so as to compensate for the effects ofdiclofenac on the GHB salt when concomitantly administered.

Another embodiment of the present invention is a method for treating apatient who is suffering from narcolepsy wherein said patient iscurrently taking or has been prescribed GHB or a salt thereof,comprising determining if the patient is taking or has also beenprescribed valproate or diclofenac; and adjusting the dose of the GHB orGHB salt to compensate for the effect caused by valproate or diclofenac.In certain embodiments, the method additionally comprises administeringthe adjusted dose to the patient.

Another embodiment of the present invention is a method for treating apatient who is suffering from excessive daytime sleepiness, cataplexy,sleep paralysis, apnea, narcolepsy, sleep time disturbances, hypnagogichallucinations, sleep arousal, insomnia, and nocturnal myoclonus with asalt of gamma GHB, wherein said patient is also being treated withvalproate or diclofenac, comprising: administering to the patient adaily dose of a GHB salt wherein said daily dose is administered at anamount sufficient to reduce or eliminate additive effects.

The embodiments of the present invention can administer the GHB at alevel of between 1 and 4.5 grams/day or between 6 and 10 grams/day. Theconcentration of the formulation can be between 350-750 mg/ml or 450-550mg/ml and a pH between 6-10 or 6.5-8.

Another embodiment of the present invention is a method for treating apatient who is suffering from narcolepsy, comprising: administering asalt of GHB or a salt thereof to a patient or determining whether thepatient is currently on a GHB drug regimen; determining if the patientis also being administered ibuprofen; and advising a patient to cease orceasing the administration of ibuprofen. In some embodiments, patientsbenefiting from this directive when the patient has will have a renalimpairment.

Another embodiment of the present invention is a method for treating apatient who is suffering from narcolepsy, comprising: administering atherapeutically effective amount of a formulation containing GHB or asalt thereof to a patient at a concentration of between 450 and 550mg/ml and a pH between 6 and 8, said formulation being administeredbefore bed and 1-2 hours thereafter; determining if the patient is alsobeing administered valproate; warning of a potential drug/druginteraction due to the combination of valproate and GHB; and reducingthe dose of the GHB or GHB salt at least 15% to compensate for theeffect caused by valproate. Another embodiment of the present inventionis a method for treating a patient who is suffering from narcolepsy,comprising: administering a therapeutically effective amount of aformulation containing GHB or a salt thereof to a patient at aconcentration of between 450 and 550 mg/ml and a pH between 6 and 8,said formulation being administered before bed and 1-2 hours thereafter;determining if the patient is also being administered diclofenac;warning of a potential drug/drug interaction due to the combination ofdiclofenac and the GHB salt; and increasing the dose of the GHB salt atleast 15% to compensate for the effect caused by diclofenac.

In each of the embodiments of the invention the method includesadministering GHB at between 1 and 4.5 grams/day or between 6 and 10grams/day and at a concentration of between 350-750 or 450-550 mg/ml,and a pH between 6-10 or between 6.5-8. In further embodiments thevalproate or diclofenac is administered within three days, one or twoweeks (before or after) of GHB administration. In another embodiment,the present invention is a method wherein aspirin is also administeredto the patient, especially with valproate.

In a further embodiment the method can include administering GHB as asingle salt or a mixture of salts of GHB selected from the groupconsisting of a sodium salt of hydroxybutyrate (Na.GHB), a potassiumsalt of gamma-hydroxybutyrate (K.GHB), a magnesium salt ofgamma-hydroxybutyrate (Mg.(GHB)₂), and a calcium salt ofgamma-hydroxybutyrate (Ca.(GHB)₂).

In a further embodiment the method can include administering GHB to apatient suffering from excessive daytime sleepiness, comprising:administering a therapeutically effective amount of GHB to the patient;determining if the patient has concomitant administration of an MCTinhibitor; and adjusting the GHB dose or ceasing administering of theMCT inhibitor to maintain the effect of the GHB.

In any of the versions of the invention, the methods optionally furtherinclude administering aspirin to the patient.

In a further embodiment the method of administering GHB to a patient inneed thereof comprises administering to the patient a therapeuticallyeffective amount of GHB while avoiding concomitant of a diclofenac orvalproate.

Another embodiment of the invention comprises a method of administeringGHB or a salt thereof (GHB) to a patient with narcolepsy, wherein saidpatient is also in need of diclofenac, comprising administering to thepatient a daily dosage of between 6 g and 10 g GHB or a GHB salt per daywhile avoiding diclofenac concomitant administration, and any one ormore of the following: (a) advising the patient that diclofenac shouldbe avoided or discontinued, (b) advising the patient that concomitantadministration of GHB with drugs that are MCT inhibitors can alter thetherapeutic effect or adverse reaction profile of GHB, (c) advising thepatient that concomitant administration of GHB with diclofenac can alterthe therapeutic effect or adverse reaction profile of GHB, (d) advisingthe patient that use of GHB in patients being treated with diclofenac iscontraindicated, (e) advising the patient that concomitantadministration of GHB and diclofenac resulted in an decrease in exposureto GHB, or (f) advising the patient MCT inhibitors should be used withcaution in patients receiving GHB due to the potential for increased GHBclearance.

Another embodiment of the invention comprises a administering GHB to apatient with narcolepsy, wherein said patient is also in need ofvalproate, comprising administering to the patient a daily dosage ofbetween 6 g and 10 g GHB per day while avoiding valproate concomitantadministration, and any one or more of the following: (a) advising thepatient that valproate should be avoided or discontinued, (b) advisingthe patient that concomitant administration of GHB with drugs that areMCT inhibitors can alter the therapeutic effect or adverse reactionprofile of GHB, (c) advising the patient that concomitant administrationof GHB with valproate can alter the therapeutic effect or adversereaction profile of GHB, (d) advising the patient that use of GHB inpatients being treated with valproate is contraindicated, (e) advisingthe patient that concomitant administration of GHB and valproateresulted in an increase in exposure to GHB, or (f) advising the patientthat MCT inhibitors should be used with caution in patients receivingGHB due to the potential for increased GHB clearance.

In another embodiment, the present invention is a method fordistributing a drug containing GHB or a salt thereof to an approvedpharmacy, the method comprising: identifying an approved pharmacy thathas an established management system to dispense information concerningthe risks associated with ingesting a MCT inhibitor concomitantly tosaid drug to patients that are prescribed said drug; providing saidpharmacy with said information related to the risks; and authorizingdistribution of said drug to said pharmacy, wherein said pharmacydispenses the drug with said information when filling a prescription forsaid drug. The method may also comprise including an electronic orwritten alert, which can explain the risks, to employees to dispensesaid information with said drug when prescriptions are filled. Also, theinformation can be dispensed when a subject refills said prescription.The warnings would be as recited above.

The methods of the present invention may include a warning for patientsnot to operate hazardous machinery, including automobiles or airplanes,until they are reasonably certain that GHB does not affect themadversely and not to engage in hazardous occupations or activitiesrequiring complete mental alertness or motor coordination, such asoperating machinery or a motor vehicle or flying an airplane, for atleast 6, 7, 8 or 9 hours after taking the second nightly dose of GHB.Any information dispensed with said drug advises patients of thepotential for enhanced potency of said drug if said patients also takevalproate or advises patients of the potential for decreased potency ofsaid drug if said patients also take diclofenac.

Another embodiment of the present invention is a method of administeringGHB to a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of GHB while avoidingconcomitant administration of diclofenac or valproate.

The invention may also comprise a method for reducing the effects of GHBtoxicity in a patient in need thereof, comprising administering to saidpatient an effective amount of diclofenac such that the toxic effects ofGHB are reduced. It may also comprise a method for potentiating thebeneficial effects of GHB in a patient in need thereof comprisingconcomitantly administering to said patient an effective amount ofvalproate such that the beneficial effects of GHB are increased.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows change from baseline figure (LS mean with 95% CI) for Powerof Attention (ms) (PD Completer Population). Treatment A=diclofenacplacebo+Xyrem®. Treatment B=diclofenac+Xyrem®. TreatmentC=diclofenac+Xyrem® placebo.

FIG. 2 shows change from baseline figure (LSmean with 95% CI) for DigitVigilance Accuracy (%) (PD Completer Population).

FIG. 3 shows change from baseline figure (LSmean with 95% CI) for DigitVigilance Mean Reaction Time (ms) (PD Completer Population).

FIG. 4 shows change from baseline figure (LSmean with 95% CI) for ChoiceReaction Time Mean (ms) (PD Completer Population).

FIG. 5 shows change from baseline figure (LSmean with 95% CI) forContinuity of Attention (#) (PD Population). Treatment A=Xyrem®.Treatment B=Xyrem® placebo. Treatment C=valproate.

FIG. 6 shows change from baseline figure (LSmean with 95% CI) for SimpleReaction Time Mean (ms) (PD Population).

FIG. 7 shows change from baseline figure (LSmean with 95% CI) for DigitVigilance Accuracy (%) (PD Population).

FIG. 8 shows change from baseline figure (LSmean with 95% CI) forTracking Distance from Target (mm) (PD Population).

FIG. 9 shows change from baseline figure (LSmean with 95% CI) forNumeric Working Memory Sensitivity Index (#) (PD Population).

FIG. 10 shows change from baseline figure (LSmean with 95% CI) forNumeric Working Memory Mean Reaction Time (ms) (PD Population).

DETAILED DESCRIPTION OF THE INVENTION

The following patents and applications are hereby incorporated byreference in their entireties for all purposes: U.S. Pat. Nos.6,472,431, 6,780,889, 7,262,219, 7,851,506, 8,263,650, 8,324,275;7,895,059; 7,797,171; 7,668,730; 7,765,106; 7,765,107; 61/317,212, Ser.Nos. 13/071,369, 13/739,886, 12/264,709, PCT/US2010/033572,PCT/US2009/061312, 2009/0137565; and 2012/0076865. The following patentsare also incorporated by reference: U.S. Pat. No. 5,380,937; U.S. Pat.No. 4,393,236 German Patent DD 237,309 A1; and British Pat. No. 922,029.

Objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the inventionwill become apparent to those skilled in the art from this detaileddescription.

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

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In the specification and claims that follow, references will be made toa number of terms which shall be defined to have the following meaning.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. The terms “comprising”, “having”, “including”,and “containing” are to be construed as open-ended terms (i.e., meaning“including, but not limited to”).

“Concomitant” and “concomitantly” as used herein refer to theadministration of at least two drugs to a patient either subsequently,simultaneously, or consequently within a time period during which theeffects of the first administered drug are still operative in thepatient. Thus, if the first drug is, e.g., Xyrem®, or GHB, and thesecond drug is valproate, the concomitant administration of the seconddrug occurs within two weeks, preferably within one week or even threedays, before or after the administration of the first drug.

“Dosage amount” means an amount of a drug suitable to be taken during afixed period, usually during one day (i.e., daily).

“Dosage amount adapted for oral administration” means a dosage amountthat is of an amount deemed safe and effective for the particularpatient under the conditions specified. As used herein and in theclaims, this dosage amount is determined by following therecommendations of the drug manufacturer's Prescribing Information asapproved by the US Food and Drug Administration.

“Dosing regimen” means the dose of a drug taken at a first time by apatient and the interval (time or symptomatic) and dosage amounts atwhich any subsequent doses of the drug are taken by the patient. Eachdose may be of the same or a different dosage amount.

A “dose” means the measured quantity of a drug to be taken at one timeby a patient.

A “patient” means a human in need of medical treatment. In oneembodiment medical treatment can include treatment of an existingcondition, such as a disease or disorder, prophylactic or preventativetreatment, or diagnostic treatment. In another embodiment, medicaltreatment also includes administration to treat excessive daytimesleepiness, cataplexy, sleep paralysis, apnea, narcolepsy, sleep timedisturbances, hypnagogic hallucinations, sleep arousal, insomnia, andnocturnal myoclonus.

“Providing” means giving, administering, selling, distributing,transferring (for profit or not), manufacturing, compounding, ordispensing.

The terms “therapeutically effective amount,” as used herein, refer toan amount of a compound sufficient to treat, ameliorate, or prevent theidentified disease or condition, or to exhibit a detectable therapeutic,prophylactic, or inhibitory effect. The effect can be detected by, forexample, an improvement in clinical condition, or reduction in symptoms.The precise effective amount for a subject will depend upon thesubject's body weight, size, and health; the nature and extent of thecondition; and the therapeutic or combination of therapeutics selectedfor administration. Where a drug has been approved by the U.S. Food andDrug Administration (FDA), a “therapeutically effective amount” refersto the dosage approved by the FDA or its counterpart foreign agency fortreatment of the identified disease or condition.

“Side effect” means a secondary effect resulting from taking a drug. Thesecondary effect can be a negative (unfavorable) effect (i.e., anadverse side effect) or a positive (favorable) effect.

Pharmacokinetic parameters referred to herein describe the in vivocharacteristics of drug (or a metabolite or a surrogate marker for thedrug) over time. These include plasma concentration (C), as well asC_(max), C_(n), C₂₄, T_(max), and AUC. The term “T_(max)” refers to thetime from drug administration until C_(max) is reached. “AUC” is thearea under the curve of a graph of the measured plasma concentration ofan active agent vs. time, measured from one time point to another timepoint. For example AUC_(0-t) is the area under the curve of plasmaconcentration versus time from time 0 to time t, where time 0 is thetime of initial administration of the drug. Time t can be the last timepoint with measurable plasma concentration for an individualformulation. The AUC_(0-infin.) or AUC_(0-INF) is the calculated areaunder the curve of plasma concentration versus time from time 0 to timeinfinity. In steady-state studies, AUC_(0-.tau.) is the area under thecurve of plasma concentration over the dosing interval (i.e., from time0 to time .tau. (tau), where tau is the length of the dosing interval.

It may be advantageous to incorporate a pharmacy management system intothe method of the present invention. Pharmacy management systems arecomputer-based systems that are used by commercial pharmacies to manageprescriptions and to provide pharmacy and medical personnel withwarnings and guidance regarding drugs being administered to patients.Such systems typically provide alerts warning either or both of healthcare providers and patients when a drug that may be harmful to theparticular patient is prescribed. For example, such systems can providealerts warning that a patient has an allergy to a prescribed drug, or isreceiving concomitant administration of a drug that can have a dangerousinteraction with a prescribed drug. U.S. Pat. Nos. 7,895,059; 7,797,171;7,668,730; 7,765,106; 7,765,107; 5,758,095, 5,833,599, 5,845,255,6,014,631, 6,067,524, 6,112,182, 6,317,719, 6,356,873, and 7,072,840,each of which is incorporated herein by reference, disclose variouspharmacy management systems and aspects thereof. Example pharmacymanagement systems are now commercially available, e.g., CENTRICITYPharmacy from BDM Information Systems Ltd., General Electric Healthcare,Waukesha, Wis., Rx30 Pharmacy Systems from Transaction Data Systems,Inc., Ocoee, Fla., SPEED SCRIPT from Digital Simplistics, Inc., Lenexa,Kans., and various pharmacy management systems from OPUS-ISM, Hauppauge,N.Y.

In some embodiments, a pharmacy management system may be required orpreferred as part of a drug distribution program. For example, thepresent invention includes a method for distributing a drug containingGHB or a salt thereof to an approved pharmacy, the method comprising:(1) Identifying an approved pharmacy that has an established managementsystem to dispense information concerning the risks associated withingesting a MCT inhibitors concomitantly to said drug to patients thatare prescribed said drug; (2) Providing said pharmacy with saidinformation related to the risks; and (3) Authorizing distribution ofsaid drug to said pharmacy, wherein said pharmacy dispenses the drugwith said information when filling a prescription for said drug. Theestablished management system may include an electronic alert toemployees to dispense said information with said drug when prescriptionsare filled. Such information may be dispensed in written form, forexample in a brochure explaining the risks of concomitant ingestion ofGHB and an MCT inhibitor such as diclofenac, valproate, or ibuprofen orcombinations thereof. For example, the information dispensed with GHBmay advise a patient of the potential for enhanced potency of GHB if thepatient also takes valproate. Alternatively, or in addition thereto, theinformation dispensed with GHB may advise a patient of the potential fordecreased potency of GHB if the patient also takes diclofenac. Suchinformation may also be dispensed in verbal form. Distributors maymaintain a directory of approved pharmacies, for example in a computerreadable storage medium, to further ensure that GHB is dispensed only topatients who are advised of the additive effects.

In addition, the system can prevent the dispensing of GHB or saltthereof until proper testing or confirmation is obtained that thepatient is not taking or going to take valproate or diclofenacconcomitantly with GHB. Alternatively, the patient can be warned of theadverse effect and instructed to modify the dose of GHB to accommodatethe increased or reduced effects of GHB due to valproate or diclofenac.

A pharmacy management system of the present invention can be a REMSsystem as shown in U.S. Pat. Nos. 7,895,059; 7,797,171; and 7,668,730and also include monitoring for concomitant use of diclofenac,valproate, or ibuprofen, or combinations thereof. Warnings may beadministered through the existing pharmacy management system asdescribed in the patents above.

One embodiment of the present invention, without being limited bytheory, is the discovery of drug interactions that change either, orboth, the efficacy or safety profile of GHB. The three compounds arevalproate, diclofenac, and ibuprofen or combinations thereof. To achievethe above benefits, GHB of the present invention can be administered ina reduced amount when a second compound, such as valproate, isconcomitantly administered with GHB. It can also be administered in anincreased amount to overcome any effects of diclofenac. The compoundscan also be avoided or discontinued to prevent unsafe concomitantadministration.

In one embodiment of the present invention, concomitant administrationof GHB with other agents is monitored and potential changes to the dosesof GHB are made, or changes in the administration of other compounds aremade. In one embodiment of the present invention, when GHB wasconcomitantly administered with ibuprofen, there were pharmacokinetic(PK) changes consistent with monocarboxylic transporter (MCT) inhibitionand renal excretion of GHB doubled (statistically significant). Plasmalevels were about ˜5% lower, which was statistically significant. Inanother embodiment of the present invention, when GHB and Diclofenac areconcomitantly administered, PD effects were significantly reduced. Inanother embodiment of the present invention, when GHB and divalproatewere concomitantly administered, PK showed both MCT and GHBdehydrogenase inhibition, with the latter predominating. MCT inhibitioncaused renal clearance to be increased 30% (statistically significant).GHB dehydrogenase inhibition caused systemic exposure (plasma AUC) to beincreased 26%. Both measures are statistically significant and outsideFDA “equivalence window”. PD shows more pronounced effects withconcomitant administration.

One embodiment is a method of administering a therapeutically effectiveamount of GHB to a patient in need of treatment, such as withnarcolepsy, the invention provides an improvement that comprisesavoiding or discontinuing administration of a compound that affects GHBpotency and administering a therapeutically effective amount of GHB. Thecompound can be diclofenac or valproate and they can alter thetherapeutic effect or adverse reaction profile of GHB.

Gamma Hydroxybutyrate (GHB)

GHB (also called oxysorbate or oxybate) is approved in the United States(US) for the treatment of excessive daytime sleepiness (EDS) and for thetreatment of cataplexy, both in patients with narcolepsy. GHB iscommercially sold as Xyrem® sodium oxybate by Jazz Pharmaceuticals.Sodium oxybate is the sodium salt of the endogenous neurotransmittergamma hydroxybutyrate (GHB), which is found in many tissues of the body.“GHB”, oxybate, a GHB salt or Xyrem® will be used to refer to theseactive forms. It can be used as a sodium, calcium, potassium, ormagnesium salt. See U.S. patent application Ser. No. 13/739,886.

GHB is present, for example, in the mammalian brain and other tissues.In the brain, the highest GHB concentration is found in the hypothalamusand basal ganglia and GHB is postulated to function as aneurotransmitter. The neuropharmacologic effects of GHB includeincreases in brain acetylcholine, increases in brain dopamine,inhibition of GABA-ketoglutarate transaminase and depression of glucoseutilization but not oxygen consumption in the brain. GHB is converted tosuccinate and then metabolized via the Krebs cycle. Clinical trials haveshown that GHB increases delta sleep and improves the continuity ofsleep (Laborit, 1973; Lapierre et al., 1988; Lapierre et al., 1990;Yamada et al., 1967; Scharf, 1985).

GHB treatment substantially reduces the signs and symptoms ofnarcolepsy, i.e. excessive daytime sleepiness, cataplexy, sleepparalysis, apnea, narcolepsy, sleep time disturbances, hypnagogichallucinations, sleep arousal, insomnia, and nocturnal myoclonus. Inaddition, GHB increases total sleep time and REM sleep, and it decreasesREM latency (Mamelak et al, 1973; Yamada et al., 1967; Bedard et al.,1989), reduces sleep apnea (Scrima et al., 1987), and improves generalanesthesia (Hasenbos and Gielen, 1985).

GHB has several clinical applications other than narcolepsy and sleepdisorders. GHB has been reported to reduce alcohol craving, the numberof daily drinks consumed, and the symptoms of alcohol withdrawal inpatients (Gallimberti et al., 1989; Gallimberti et al., 1992; Gessa etal., 1992). GHB has been used to decrease the symptoms of opiatewithdrawal, including both heroin and methadone withdrawal (Gallimbertiet al., 1994; Gallimberti et al., 1993). It has analgesic effects thatmake it suitable as a pain reliever (U.S. Pat. No. 4,393,236).Intravenous administration of GHB has been reported to reduceintracranial pressure in patients (Strong, A. 1984). Also,administration of GHB was reported to increase growth hormone levels inpatients (Gessa et al, 1994).

A good safety profile for GHB consumption, when used long term fortreatment of narcolepsy has been reported. Patients have been safelytreated for many years with GHB without development of tolerance(Scharf, 1985). Clinical laboratory tests carried out periodically onmany patients have not indicated organ or other toxicities (Lammers,1993; Scrima, 1990; Scharf, 1985; Mamelack, 1977; Mamelak, 1979; Gessa,1992). The side effects of GHB treatment have been minimal in incidenceand degree of severity, though they include sleepwalking, enuresis,headache, nausea and dizziness (Broughton and Mamelak, 1979; Mamelak etal., 1981; Mamelak et al., 1977; Scrima et al., 1989; Scrima et al.,1990; Scharf et al., 1985). Therefore, it is critical to identifyadverse drug-drug interactions to maintain the positive safety profilefor GHB.

GHB Pharmacology

GHB has at least two distinct binding sites (See Wu, et al., 2004) inthe central nervous system. GHB is an agonist at the GHB receptor, whichis excitatory, (Cash et al., 2009) and it is a weak agonist at the GABABreceptor, which is inhibitory. GHB acts in a similar fashion to someneurotransmitters in the mammalian brain and is probably synthesizedfrom GABA in GABAergic neurons, and released when the neurons fire. Iftaken orally, GABA itself does not effectively cross theblood-brain-barrier. (See Kuriyama et al., 2005).

GHB induces the accumulation of either a derivative of tryptophan ortryptophan itself in the extracellular space, possibly by increasingtryptophan transport across the blood-brain barrier. The blood contentof certain neutral amino-acids, including tryptophan, is also increasedby peripheral GHB administration. GHB-induced stimulation of tissueserotonin turnover may be due to an increase in tryptophan transport tothe brain and in its uptake by serotonergic cells. As the serotonergicsystem may be involved in the regulation of sleep, mood, and anxiety,the stimulation of this system by high doses of GHB may be involved incertain neuropharmacological events induced by GHB administration.

However, at therapeutic doses, GHB reaches much higher concentrations inthe brain and activates GABAB receptors, which are primarily responsiblefor its sedative effects. (See Dimitrijevic et al., 2005). GHB'ssedative effects are blocked by GABAB antagonists.

The role of the GHB receptor in the behavioral effects induced by GHB ismore complex. GHB receptors are densely expressed in many areas of thebrain, including the cortex and hippocampus, and these are the receptorsthat GHB displays the highest affinity for. There has been somewhatlimited research into the GHB receptor; however, there is evidence thatactivation of the GHB receptor in some brain areas results in therelease of glutamate, the principal excitatory neurotransmitter. Drugsthat selectively activate the GHB receptor cause absence seizures inhigh doses, as do GHB and GABA(B) agonists. (See Banerjee et al., 1995.)

Activation of both the GHB receptor and GABA(B) is responsible for theaddictive profile of GHB. GHB's effect on dopamine release is biphasic.(See Hechler et al., 1991). Low concentrations stimulate dopaminerelease via the GHB receptor. (See Maitre et al., 1990). Higherconcentrations inhibit dopamine release via GABA(B) receptors as doother GABA(B) agonists such as baclofen and phenibut. (See Smolders etal., 1995). After an initial phase of inhibition, dopamine release isthen increased via the GHB receptor. Both the inhibition and increase ofdopamine release by GHB are inhibited by opioid antagonists such asnaloxone and naltrexone. Dynorphin may play a role in the inhibition ofdopamine release via kappa opioid receptors. (See Mamelak 1989).

This may explain the paradoxical mix of sedative and stimulatoryproperties of GHB, as well as the so-called “rebound” effect,experienced by individuals using GHB as a sleeping agent, wherein theyawake suddenly after several hours of GHB-induced deep sleep. That is tosay that, over time, the concentration of GHB in the system decreasesbelow the threshold for significant GABAB receptor activation andactivates predominantly the GHB receptor, leading to wakefulness.However, one embodiment of the present invention is the unexpecteddiscovery that drugs change the PD profile of GHB to alter its effectsand its safety profile. Example drugs are include valproate anddiclofenac. It is important for efficacy safety purposes that the effectof GHB be maintained consistently and not subject to variation due tothe effects of other drugs.

Both of the metabolic breakdown pathways shown for GHB can run in eitherdirection, depending on the concentrations of the substances involved,so the body can make its own GHB either from GABA or from succinicsemialdehyde. Under normal physiological conditions, the concentrationof GHB in the body is rather low, and the pathways would run in thereverse direction to what is shown here to produce endogenous GHB.However, when GHB is consumed for recreational or health promotionpurposes, its concentration in the body is much higher than normal,which changes the enzyme kinetics so that these pathways operate tometabolize GHB rather than produce it.

The pharmacokinetics of GHB have been investigated in alcohol dependentpatients (Ferrara et al., 1992) and in normal healthy males (Palatini etal., 1993) after oral administration. GHB possesses a rapid onset andshort pharmacological effect (Ferrara et al., 1992; Palatine et al.,1993; Lettieri and Fung, 1978; Arena and Fung, 1980; Roth and Giarman,1966; Vickers, 1969; Lee, 1977). In alcohol dependent patients, GHBabsorption into and elimination from the systemic circulation were fastprocesses. Virtually no unchanged drug could be recovered in the urine.There were preliminary indications that the pharmacokinetics of GHBmight be non-linear or dose-dependent (Ferrara et al., 1992). In thehealthy volunteers study, the pharmacokinetics of three rising GHB doses(12.5, 25, and 50 mg/kg) were investigated. These findings indicate thatboth the oral absorption and elimination processes of GHB werecapacity-limited though the degree of dose dependency was moderate(Palatini et al., 1993).

Methods of making GHB salts are described, for example, in U.S. Pat. No.4,393,236, and U.S. patent application Ser. No. 13/739,886 which areincorporated herein by reference.

It has been discovered that there are unexpected drug-drug interactions(DDI) between GHB and common drugs frequently prescribed for otherailments. It is one goal of the present invention to warn when thoseinteractions may affect the safety profile of GHB. In one embodiment ofthe present invention, drugs that may affect GHB administration includevalproate, diclofenac, and ibuprofen and combinations thereof.

GHB is a central nervous system (CNS) depressant. Alcohol and sedativehypnotics are contraindicated in patients who are using GHB. Theconcurrent use of GHB with other CNS depressants, including but notlimited to opioid analgesics, benzodiazepines, sedating antidepressantsor antipsychotics, general anesthetics, muscle relaxants, and/or illicitCNS depressants, may increase the risk of respiratory depression,hypotension, profound sedation, syncope, and death. If use of these CNSdepressants in combination with GHB is required, dose reduction ordiscontinuation of one or more CNS depressants (including GHB) should beconsidered. In addition, if short-term use of an opioid (e.g. post- orperioperative) is required, interruption of treatment with GHB should beconsidered. See the package insert for Xyrem®.

GHB may impair respiratory drive, especially with overdoses associatedwith interactions with other drugs and alcohol. Since valproate maypotentiate the effect of GHB, a warning should accompany any use ofvalproate and GHB as stated herein. The warning should address the useof additional drugs that may further enhance the effect of GHB, such asalcohol or aspirin, for example.

Healthcare providers should caution patients about operating hazardousmachinery, including automobiles or airplanes, until they are reasonablycertain that GHB does not affect them adversely (e.g., impair judgment,thinking, or motor skills). Patients should not engage in hazardousoccupations or activities requiring complete mental alertness or motorcoordination, such as operating machinery or a motor vehicle or flyingan airplane, for at least 6, 7, 8 or 9 hours after taking the secondnightly dose of GHB. Patients should be queried about potential adverseevents, such as excessive daytime sleepiness, CNS depression relatedevents, etc. upon initiation of GHB therapy and periodically thereafter.These queries should include info regarding additional medication suchas diclofenac and valproate for example. See the Xyrem® package insert.

In one embodiment described herein, patients are warned that combinationof GHB with valproate can increase plasma levels and potentiate theactivity of GHB and exacerbate all the effects and adverse eventassociated with GHB. These effects include the intended effects ofdrowsiness, sedation, and sleep and typically unintended events such asdepressed respiration, CNS depression, excessive drowsiness, hepaticimpairment, and depression, among other things.

In another embodiment, diclofenac mitigates and protects against thepharmacodynamic effects the effects of GHB. However, the mixture of GHBand diclofenac does not affect sleepiness and does not make a patientmore attentive. Without wishing to be bound by theory, the effects maybe due to the interaction between diclofenac and the GHB receptor inlieu of the MCT inhibitor activity.

Typical concentrations of GHB formulations are shown in U.S. Pat. Nos.8,263,650 and 8,324,275, for example. They include minimumconcentrations starting from 150 mg/ml to 450 mg/ml (at 10 mg/mlincrements) and increasing to 600 mg/ml to 750 mg/ml (at 10 mg/mlincrements) as a maximum. So, a broad range would include 150-750 mg/mland any range within the broad range using 10 mg/ml increments. Oneembodiment of the invention is a range of 350-750 mg/ml and another is450-550 mg/ml GHB. One embodiment of the present invention uses a GHBformulation with a pH range of 6-10, another uses a pH range of between6.5-8. For example, a minimum concentration includes 350, 360, 370, 380mg/ml, and so on up to at least 730, 740, and 750 mg/ml and allconcentrations (measured in 10 mg/ml increments in between).

pH adjusting agents can include acids, bases and many of the compoundsfound in U.S. Pat. No. 8,263,650. In some embodiments the pH adjustingagent is an acid selected from the group of: acetic, acetylsalicylic,barbital, barbituric, benzoic, benzyl penicillin, boric, caffeine,carbonic, citric, dichloroacetic, ethylenediaminetetra-acetic acid(EDTA), formic, glycerophosphoric, glycine, lactic, malic, mandelic,monochloroacetic, oxalic, phenobarbital, phenol, picric, propionic,saccharin, salicylic, sodium dihydrogen phosphate, succinic,sulfadiazine, sulfamerazine, sulfapyridine, sulfathiazole, tartaric,trichloroacetic, and the like, or inorganic acids such as hydrochloric,nitric, phosphoric or sulfuric, and the like.

GHB is commercially available as a sodium salt, however, it can also beformulated as a mixture of salts as shown in U.S. Ser. No. 13/739,886,which is incorporated by reference as stated above. For example, themixture comprises one, two, or three or more salts selected from thegroup consisting of a sodium salt of hydroxybutyrate (Na.GHB), apotassium salt of gamma-hydroxybutyrate (K.GHB), a magnesium salt ofgamma-hydroxybutyrate (Mg.(GHB)₂), and a calcium salt ofgamma-hydroxybutyrate (Ca.(GHB)₂). The different salts may be present indifferent percentages. For example, in certain embodiments, thepharmaceutical composition comprises Na.GHB, K.GHB, and Ca.(GHB)₂. Incertain embodiments, the Na.GHB salt is present in a wt/wt % of about 5%to about 40%, the K.GHB salt is present in a wt/wt % of about 10% toabout 40%, and the Ca.(GHB)₂ salt is present in a wt/wt % of about 20%to about 80%. In certain embodiments, the Na.GHB, K.GHB, and Ca.(GHB)₂salts are present in a wt/wt % ratio of about 11%: 39%: 50%,respectively.

Valproic Acid

Valproic acid (VPA, also called valproate or divalproex), an acidicchemical compound, has found clinical use as an anticonvulsant andmood-stabilizing drug, primarily in the treatment of epilepsy, bipolardisorder, and, less commonly, major depression. See G. Rosenberg, Cell.Mol. Life Sci. 64 (2007) 2090-2103. It is also used to treat migraineheadaches and schizophrenia. A typical dose of valproate varies byindication. Dosages for seizures are between 10 to 15 mg/kg/day, withpotential increases of 5 to 10 mg/kg/day. VPA is a liquid at roomtemperature, but it can be reacted with a base such as sodium hydroxideto form the salt sodium valproate, which is a solid. The acid, salt, ora mixture of the two (valproate semisodium, divalproate) are marketedunder the various brand names Depakote, Depakote ER, Depakene, DepakeneCrono (extended release in Spain), Depacon, Depakine, Valparin andStavzor.

Valproate is believed to affect the function of the neurotransmitterGABA in the human brain, making it an alternative to lithium salts intreatment of bipolar disorder. Its mechanism of action includes enhancedneurotransmission of GABA (by inhibiting GABA transaminase, which breaksdown GABA). However, several other mechanisms of action inneuropsychiatric disorders have been proposed for valproic acid inrecent years. See Rosenberg G (2007). “The mechanisms of action ofvalproate in neuropsychiatric disorders: can we see the forest for thetrees?”. Cellular and Molecular Life Sciences 64 (16): 2090-103.

Valproic acid also blocks the voltage-gated sodium channels and T-typecalcium channels. These mechanisms make valproic acid a broad-spectrumanticonvulsant drug. Valproic acid is an inhibitor of the enzyme histonedeacetylase 1 (HDAC1), hence it is a histone deacetylase inhibitor.Valproic acid may interact with carbamazepine, as valproates inhibitmicrosomal epoxide hydrolase (mEH), the enzyme responsible for thebreakdown of carbamazepine-10,11 epoxide (the main active metabolite ofcarbamazepine) into inactive metabolites. (See Gonzalez, Frank J.;Robert H. Tukey (2006). “Drug Metabolism”. In Laurence Brunton, JohnLazo, Keith Parker (eds.). Goodman & Gilman's The Pharmacological Basisof Therapeutics (11th ed.). New York: McGraw-Hill. pp. 79.) Byinhibiting mEH, valproic acid causes a buildup of the active metabolite,prolonging the effects of carbamazepine and delaying its excretion.Valproic acid also decreases the clearance of amitriptyline andnortriptyline.

Aspirin may decrease the clearance of valproic acid, leading tohigher-than-intended serum levels of the anticonvulsant. Also, combiningvalproic acid with the benzodiazepine clonazepam can lead to profoundsedation and increases the risk of absence seizures in patientssusceptible to them.

Valproic acid and sodium valproate reduce the apparent clearance oflamotrigine (lamictal). In most patients, the lamotrigine dosage forcoadministration with valproate must be reduced to half the monotherapydosage.

Valproic acid is contraindicated in pregnancy, as it decreases theintestinal reabsorption of folate (folic acid), which leads to neuraltube defects. Because of a decrease in folate, megaloblastic anemia mayalso result. Phenytoin also decreases folate absorption, which may leadto the same adverse effects as valproic acid.

Valproic acid, 2-propylvaleric acid, is synthesized by the alkylation ofcyanoacetic ester with two moles of propylbromide, to givedipropylcyanoacetic ester. Hydrolysis and decarboxylation of thecarboethoxy group gives dipropylacetonitrile, which is hydrolyzed intovalproic acid. See U.S. Pat. Nos. 3,325,361 and 4,155,929 and GB Pat.Nos. 980279 and 1522450. See also, T. R. Henry, “The History ofValproate in Clinical Neuroscience.” Psychopharmacology bulletin (2003)37 (Suppl 2):5-16.

Diclofenac

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) taken toreduce inflammation and as an analgesic reducing pain in certainconditions. Diclofenac is used to treat pain, inflammatory disorders,and dysmenorrhea and is a commonly used NSAID. See Auler et al.,Brazilian Jour. Med. Bio. Res., (1977) 30:369-374 and Hasan, et al., andPakistan Jour. Pharmaceutical Sciences, vol. 18, No. 1, January 2005, pp18-24 both are hereby incorporated by reference in their entireties.

The name is derived from its chemical name: 2-(2,6-dichloranilino)phenylacetic acid, it may be supplied as either the sodium or potassiumsalt. Diclofenac is available as a generic drug in a number offormulations; including Dichlofenac diethylammonium applied topically tojoints. Over-the-counter (OTC) use is approved in some countries forminor aches and pains and fever associated with common infections.

Diclofenac is typically absorbed readily, but absorption is delayed uponadministration with food. Its half-life varies from 1 to 3 hours withmean peak plasma levels of about 0.5 ug/ml to 1.0 ug/ml after 2 hours ofa single dose of 25 mg. Diclofenac binds to human serum proteins,specifically albumin. See Hasan et al 2005.

Ibuprofen

Ibuprofen (from iso-butyl-propanoic-phenolic acid) is a nonsteroidalanti-inflammatory drug (NSAID) widely prescribed for pain relief, feverreduction, and swelling. Ibuprofen was derived from propanoic acid.Originally marketed as Brufen, ibuprofen is available under a variety ofpopular trademarks, including Motrin, Nurofen, Advil, and Nuprin.Ibuprofen is used primarily for fever, pain, dysmenorrhea andinflammatory diseases such as rheumatoid arthritis. It is also used forpericarditis and patent ductus arteriosus. It is a commonly used drugcommercially available over the counter.

Nonsteroidal anti-inflammatory drugs such as ibuprofen work byinhibiting the enzyme cyclooxygenase (COX), which converts arachidonicacid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by otherenzymes to several other prostaglandins (which are mediators of pain,inflammation, and fever) and to thromboxane A2 (which stimulatesplatelet aggregation, leading to the formation of blood clots).

Like aspirin and indomethacin, ibuprofen is a nonselective COXinhibitor, in that it inhibits two isoforms of cyclooxygenase, COX-1 andCOX-2. The analgesic, antipyretic, and anti-inflammatory activity ofNSAIDs appears to operate mainly through inhibition of COX-2, whereasinhibition of COX-1 would be responsible for unwanted effects on thegastrointestinal tract. However, the role of the individual COX isoformsin the analgesic, anti-inflammatory, and gastric damage effects ofNSAIDs is uncertain and different compounds cause different degrees ofanalgesia and gastric damage.

The synthesis of this compound consisted of six steps, started with theFriedel-Crafts acetylation of isobutylbenzene. Reaction with ethylchloroacetate (Darzens reaction) gave the α,β-epoxy ester, which washydrolyzed and decarboxylated to the aldehyde. Reaction withhydroxylamine gave the oxime, which was converted to the nitrile, thenhydrolyzed to the desired acid. See U.S. Pat. No. 3,385,886.

An improved synthesis by BHC required only three steps. After a similaracetylation, hydrogenation with Raney nickel gave the alcohol, whichunderwent palladium-catalyzed carbonylation.

Valproate, diclofenac, and ibuprofen are monocarboxylate transporterinhibitors. One embodiment of the present application is a method toimprove safety by monitoring the combination of these compounds withGHB.

Monocarboxylate Transporters

Monocarboxylate transporters, or MCTs, constitute a family ofproton-linked plasma membrane transporters that carry molecules havingone carboxylate group (monocarboxylates), such as lactate and pyruvate,across biological membranes. See Halestrap A P, Meredith D (2004). “TheSLC16 gene family-from monocarboxylate transporters (MCTs) to aromaticamino acid transporters and beyond”. Pflugers Arch. 447 (5): 619-28.

MCTs are a series of transporters which move chemicals in body tissues,such as kidneys, blood/brain barrier, intestines, etc. They cantransport chemical compounds back from urine to create a higherconcentration in the blood than the urine. They can be used to treat anoverdose or to prevent excretion of a compound. They can also be used toprevent absorption or transport into the brain or gut, or excretion viathe urine. Exemplary MCT inhibitors include valproate, diclofenac, andibuprofen.

Concomitant Administration of GHB and Drug-Drug Interactions

In one embodiment of the present invention the concomitantadministration of MCT inhibitors, such as either valproate, diclofenac,or ibuprofen with GHB can effect GHB levels or activity and alter theGHB safety and efficacy profile to create an unsafe condition. Forexample, valproate can increase or prolong GHB effects and diclofenaccan reduce or shorten GHB effects. For example, if the effects areincreased, then there could be an increase of adverse events associatedwith too much GHB. Also, the effect of GHB may be prolonged to causeside effects, such as excessive daytime sleepiness (EDS), to last intothe daytime. Prolongation of the effect would counter the purpose forproviding the GHB and could create an unsafe situation for patients whowish to be alert and who may be engaged in otherwise dangerous activity.This concomitant administration can transform an otherwise safe dose ofGHB into one with safety concerns. It is a health risk to patients and amedical challenge to health care workers.

The drug-drug interaction could also reduce the effects of GHB byaltering its blood levels or otherwise. Reduction in the GHB level mayalso provide an unsafe condition due to excessive daytime sleepiness. Ineach situation, where GHB is increased, decreased or excessivelycleared, those drug-drug interactions need to be identified to a healthcare worker to adjust the dose of GHB or discontinue the use of theother compound.

As recited on the product insert for Xyrem®, healthcare providers shouldcaution patients about operating hazardous machinery, includingautomobiles or airplanes, until they are reasonably certain that GHBdoes not affect them adversely (e.g., impair judgment, thinking, ormotor skills). Patients should not engage in hazardous occupations oractivities requiring complete mental alertness or motor coordination,such as operating machinery or a motor vehicle or flying an airplane,for at least 6, 7, 8 or 9 hours after taking the second nightly dose ofGHB.

In some embodiments in which diclofenac or valproate is discontinued toavoid an adverse drug interaction, they are discontinued within at least3 days prior to or after starting GHB therapy. In various embodiments,diclofenac or valproate is discontinued within at least 4 days, or atleast 5 days, or at least 6 days, or at least 7 days (or one week), orat least 8 days, or at least 9 days, or at least 10 days, or at least 11days, or at least 12 days, or at least 13 days, or at least 14 days (ortwo weeks), or at least 15 days, or at least 16 days, or at least 17days, or at least 18 days, or at least 19 days, or at least 20 days, orat least 21 days (or three weeks) prior to or after starting GHBtherapy. In some embodiments, the diclofenac or valproate isdiscontinued no later than 2 weeks or 1 week before starting GHBtherapy.

In some embodiments, a method of optimizing GHB therapy when valproateis provided comprises titrating the dosage of GHB administered to apatient downward relative to a previously administered dosage in thepatient, so the dose does not result in an increased exposure to GHB. Insome embodiments, a method of optimizing GHB therapy when diclofenac isprovided comprises titrating the dosage of GHB administered to a patientupward relative to a previously administered dosage in the patient, sothe dose results in an effective exposure to GHB.

Thus, the present invention includes a method for treating a patient whois suffering from excessive daytime sleepiness, cataplexy, sleepparalysis, apnea, narcolepsy, sleep time disturbances, hypnagogichallucinations, sleep arousal, insomnia, and nocturnal myoclonus with asalt of gamma-hydroxybutyrate (GHB), wherein said patient is also beingtreated with valproate or diclofenac, comprising: administering to thepatient a daily dose of a GHB salt wherein said daily dose isadministered at an amount sufficient to reduce or eliminate suchadditive effects.

In one embodiment of the present invention, a reduced amount of GHB isadministered to a patient when concomitantly administered withvalproate. In another embodiment of the present invention, an increasedamount of GHB is administered to a patient when concomitantlyadministered with diclofenac.

When valproate is concomitantly administered with GHB, The amount of GHBcan be reduced at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,or 50% of the normal dose of GHB. For example, if the normal dose is 9g/day, then a dose that is adjusted to reduce the normal dose by 15% is7.65 g/day. The GHB dose reduction may be taken for one or multiple GHBdosings. For example, GHB may be administered in two doses per night fornarcolepsy. A typical adult range of doses for GHB are between 4.5 or 6g as a minimum and 8 or 10 g/day as a maximum divided into two doses.The dose recommended on the package insert and approved by the FDA isbetween 4.5 and 9.0 g/day. Typical exemplary pediatric daily doses ofGHB are between 1 g and 6 g/day for pediatric patients aged 0-6 years.Typical exemplary pediatric daily doses of GHB are between 1 g and 9g/day for pediatric patients aged 7-17 years. However, these ranges arenot absolute and can be increased or decreased by 1-2 grams in eitherdirection. One dose is typically administered prior to bed (night timesleep) and another dose administered 1-2 hours later. See the Xyrem®package insert (Xyrem® is a registered trademark of Jazz Pharmaceuticalsplc or its subsidiaries.). Either or both of the multiple doses may bereduced to present a safer administration profile. For example, thefirst dose may be reduced by the numbers referred to above or the secondmay be reduced by the same percentages, or both. Furthermore, theabsolute amount of GHB per dose or per day may be reduced at least 0.5g, 1 g, 1.5 g, 2.0 g, 2.5 g, 3.0 g, 3.5 g, or 4 g. An exemplary decreasein an adult dose would be to reduce the maximum dose to less than 8.5,8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3 g/day and so on. The minimumdose will be reduced accordingly to 4, 3.5, 3, 2.5, 2, and so on.

In one embodiment of the present invention, diclofenac may dampen ordelay the effect of GHB upon a patient during concomitantadministration. In one embodiment, it may be useful to increase theamount of GHB that is administered to the patient. For example, GHB maybe increased at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or50% of the normal dose of GHB. For example, if the normal dose is 10g/day, then a dose that is adjusted to increase the normal dose by 15%is 11.5 g/day. The GHB dose increase may be taken for one or multipleGHB dosings. For example, GHB may be administered in two doses per nightfor narcolepsy. Either, or both, of the multiple doses may be increasedto present a safer administration profile. For example, the first dosemay be increased by the numbers referred to above or the second may beincreased by the same percentages, or both. Furthermore, the absoluteamount of GHB per dose or per day may be increased at least 0.5 g, 1 g,1.5 g, 2.0 g, 2.5 g, 3.0 g, 3.5 g, or 4 g. An exemplary decrease in anadult dose would be to increase the minimum dose to 5, 5.5, 6, 6.5, 7,7.5, 8, 8.5 g/day and so on. An increase in the maximum dose would be atleast 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14 g/day and so on.

In another aspect, a package or kit is provided comprising GHB,optionally in a container, and a package insert, package label,instructions or other labelling including any one, two, three or more ofthe following information or recommendations: (a) use of diclofenac orvalproate should be avoided or discontinued, (b) concomitantadministration of GHB with drugs that are MCT inhibitors, such asdiclofenac or valproate can alter the therapeutic effect or adversereaction profile of GHB, (c) concomitant administration of GHB andvalproate resulted in an increase in exposure to GHB, (d) concomitantadministration of GHB and diclofenac resulted in a decrease in exposureto GHB, and/or (e) MCT inhibitors should be used with caution inpatients receiving GHB due to the potential for increased GHB clearance.

Alternatively, diclofenac can be administered to counteract the effectsof GHB toxicity using a reverse of the numerical relationships above.Similarly, valproate can be used to increase the effects of GHB inpatients that cannot take higher amounts of GHB. In this regard, thepresent invention includes methods for reducing the effects of GHBtoxicity in a patient in need thereof, comprising administering to saidpatient an effective amount of diclofenac such that potential toxiceffects of GHB are reduced. The present invention also includes methodsfor potentiating the beneficial effects of GHB in a patient in needthereof comprising concomitantly administering to said patient aneffective amount of valproate such that the beneficial effects of GHBare increased.

The examples below, which show drug interaction studies in healthyadults, demonstrated those instances, test conditions or metrics whichshowed a distinction between GHB and either of the test compounds,diclofenac, valproate, or ibuprofen. Additionally, drug interactionstudies in healthy adults demonstrated pharmacokinetic or clinicallysignificant pharmacodynamic interactions between GHB and diclofenac orvalproate.

Example 1

This study was designed to compare Pharmacokinetic (PK) andPharmacodynamic (PD) endpoints of Xyrem® sodium oxysorbate (GHB) withand without concomitant administration of diclofenac. A crossover designwas employed to allow within-subject comparisons of the PK and PD ofXyrem® dosed alone and in combination with diclofenac. The PK and PDeffects of Xyrem® upon those of diclofenac were also studied.

The PD parameters included a selection of automated tests of attention,information processing, working memory and skilled coordination from theCDR System. (Rapeport et al, 1996ab; Williams et al, 1996). (Wesnes etal, 1997). (Wesnes et al, 2000) (Modi et al, 2007).

Methods

This was a Phase 1, randomized, double-blind, placebo-controlled,three-period, crossover study in healthy subjects. 24 subjects wererecruited to ensure that 18 completed the study. Following Screening andBaseline procedures, eligible subjects were entered into the study andreceived one of the following treatments per period, in randomizedorder:

Diclofenac placebo administered as one capsule qid (doses separated by 4hours during the day, eg, approximately 8 am, 12 pm, 4 pm, and 8 pm) for2 days before concomitant administration day. On concomitantadministration day, one diclofenac placebo capsule administered at −1 hand 3 h, and 3 g of Xyrem® administered at 0 h and 4 h.

Diclofenac administered as 50 mg immediate-release (IR) tablet(overencapsulated) qid (doses separated by 4 hours during the day, eg,approximately 8 am, 12 pm, 4 pm, and 8 pm) for 2 days before concomitantadministration day. On concomitant administration day, 50 mg diclofenacadministered at −1 h and 3 h and 3 g of Xyrem® administered at 0 h and 4h.

Diclofenac administered as 50 mg IR tablet (overencapsulated) qid (dosesseparated by 4 hours during the day, eg, approximately 8 am, 12 pm, 4pm, and 8 pm) for 2 days before concomitant administration day. Onconcomitant administration day, 50 mg diclofenac administered at −1 hand 3 h and Xyrem® placebo (volume equivalent to 3 g of Xyrem® oralsolution) administered at 0 h and 4 h.

Subjects were randomized to one of the above treatments on Day 1,crossed over to another treatment on Day 6, and crossed over again tothe remaining treatment on Day 11 (Table 1). Subjects were dosed ingroups of up to 12. A 2-day washout period followed each of thetreatment periods. The treatments were as follows: A=Diclofenac placebo(qid 4 h apart on the 1st and 2nd day and 2 doses on the 3rd day of theperiod)+Xyrem® two 3 g doses 4 h apart on the 3rd day of the period.B=Diclofenac (50 mg qid 4 h apart on the 1st and 2nd day and 2 doses onthe 3rd day of the period)+Xyrem® two 3 g doses 4 h apart on the 3rd dayof the period. C=Diclofenac (50 mg qid 4 h apart on the 1st and 2nd dayand 2 doses on the 3rd day of the period)+Xyrem® placebo two doses 4 hapart on the 3rd day of the period. PD parameters include the following:Cognitive Drug Research (CDR) System tasks: Karolinska Sleepiness Scale(KSS), Simple Reaction Time (SRT), Digit Vigilance (DV), Choice ReactionTime (CRT), Tracking and Numeric Working Memory (NWM).

Results

Power of attention-On this measure of focussed attention and informationprocessing Xyrem® when co-dosed with diclofenac produced significantlyless impairment than Xyrem® alone at 0.5 h; while the smallerimpairments with the combination narrowly missed significance at 1 and4.5 h. Xyrem® when co-dosed with diclofenac also resulted in impairmentsat two timepoints compared to diclofenac alone which at 6.5 h wassignificant and a trend at 8 h. See FIG. 1 which shows Change fromBaseline Figure (LSmean with 95% CI) for Power of Attention (ms) (PDCompleter Population).

Digit Vigilance Accuracy-On this measure of focussed attention Xyrem®when co-dosed with diclofenac produced significantly less impairmentthan Xyrem® alone at 1 and 2.5 h. See FIG. 2 which shows Change fromBaseline Figure (LSmean with 95% CI) for Digit Vigilance Accuracy (%)(PD Completer Population).

Digit Vigilance Mean Reaction Time-On this measure of focussed attentionXyrem® when co-dosed with diclofenac produced significantly lessimpairment than Xyrem® alone at 1 and 2.5 h. See FIG. 3 which showsChange from Baseline Figure (LSmean with 95% CI) for Digit VigilanceMean Reaction Time (ms) (PD Completer Population).

Choice Reaction Time Mean-Impairments to this measure of attention andinformation processing were significantly smaller than with Xyrem® alonewhen co-dosed with diclofenac during the hour following the first doseof Xyrem®. See FIG. 4 which shows Change from Baseline Figure (LSmeanwith 95% CI) for Choice Reaction Time Mean (ms) (PD CompleterPopulation).

While diclofenac alone had no effect on sleepiness or cognitivefunction, when co-dosed with Xyrem® it significantly reduced the effectsof the compound on Power of Attention and two of the contributingscores, simple and choice reaction time; these effects being seen duringthe hour after the first dose of Xyrem®. On the other hand, there was noevidence on any measure of greater cognitive impairment or sleepinesswhen the two compounds were co-dosed.

The extent of the reductions in the impairments to the ability to focusattention and efficiently process information were quite notable, andlikely to be of clinical relevance. It is interesting that protectiveeffect of diclofenac was not seen on the subjects ratings of alertness,such a dissociation having been seen previously with haloperidol inhealthy elderly volunteers (Beuzan et al, 1991).

In conclusion, evidence of an interaction was seen in this study overthe hour following the first dose of Xyrem® on the study days, theimpairments being notably smaller when diclofenac was co-dosed withXyrem®. There was no interaction however on the feelings of sleepinessin the subjects.

Example 2

This study is designed to compare the pharmacokinetic (PK) andpharmacodynamic (PD) endpoints of Xyrem® with and withoutco-administration of divalproex sodium extended-release tablets. Thecrossover design allows within-subject comparisons of the PK and PD ofXyrem® dosed alone and in combination with divalproex sodiumextended-release tablets. PD parameters include the following: CognitiveDrug Research (CDR) System tasks: Karolinska Sleepiness Scale (KSS),Simple Reaction Time (SRT), Digit Vigilance (DV), Choice Reaction Time(CRT), Tracking and Numeric Working Memory (NWM).

The objectives of this study were to evaluate the PK and PD of Xyrem®co-administered with divalproex sodium extended-release tablets and toevaluate and compare the safety and tolerability of Xyrem® with andwithout co-administration of divalproex sodium extended-release tablets.

This was a Phase 1, randomized, double-blind, placebo-controlled,five-period, crossover study in healthy male subjects. The study wasconducted in approximately 24 healthy subjects to ensure completion of16 subjects. Following Screening and Baseline procedures, eligiblesubjects were randomized to receive Xyrem® and Xyrem® placebo in acrossover fashion in Periods 1 and 2; were dosed with divalproex sodiumextended-release tablets for 10 consecutive days in Period 3; and whilecontinuing to take divalproex sodium extended-release tablets, wererandomized to receive Xyrem® and Xyrem® placebo in a crossover fashionin Periods 4 and 5 (Table 1).

Periods 1 and 2:

Subjects were randomized to receive two 3 g doses of Xyrem® or Xyrem®placebo 4 hours apart in a crossover fashion at approximately 9 AM(first dose) and 1 PM (second dose) on Days 1 and 3. PK and PDparameters were evaluated during the 24 hours postdose.

Blood samples (4 mL) for sodium oxybate concentrations were collected atpredose and at specified time-points up to 12 hours after the first doseof Xyrem® or Xyrem® placebo on Days 1 and 3. A PD Battery including theKarolinska Sleepiness Scale, Simple Reaction Time task, Digit Vigilancetask, Choice Reaction Time task, Tracking task, and Numeric WorkingMemory task was administered at planned timepoints up to X hours afterfirst dose (X hours after second dose), and safety were monitored atspecified timepoints on Days 1 and 3 as well as throughout the periods.

Period 3:

All subjects received divalproex sodium extended-release tablets 1250 mgat approximately 8 AM on Days 5 through 14. Blood samples (4 mL) forvalproic acid concentrations were collected before the divalproex sodiumdose (to determine trough concentration for assessment of steady state)on Days 13 and 14. Safety was monitored at specified timepoints as wellas throughout the period.

Periods 4 and 5:

Subjects continued taking 1250 mg divalproex sodium extended-releasetablets at approximately 8 AM on Days 15 through 18. Subjects were alsorandomized to receive two 3 g doses of Xyrem® or Xyrem® placebo in acrossover fashion at approximately 9 am (first dose) and 1 pm (seconddose) on Days 15 and 18. The first dose of Xyrem® or Xyrem® placebo wastaken approximately 1 hour after dosing with divalproex sodiumextended-release tablets, and the second dose of Xyrem® or Xyrem®placebo was taken 4 hours after the first Xyrem®/Xyrem® placebo dose.

Blood samples (4 mL) to measure plasma sodium oxybate concentrationswere collected at pre Xyrem®/Xyrem® placebo dose and at specifiedtimepoints after the first Xyrem® or Xyrem® placebo dose on Days 15 and18. Blood samples (4 mL) to measure plasma valproic acid concentrationswere collected pre divalproex sodium dose and at specified timepointsafter the dose of divalproex sodium extended-release tablets on Day 15and 18.

The PD battery was administered on Day 15 and 18, and safety wasmonitored at specified times on Days 15 and 18 as well as throughout theperiods.

The treatments were as follows: A=Xyrem®, two 3 g doses, 4 hours apartat approximately 9 AM (1^(st) dose) and 1 PM (2^(nd) dose); B=Xyrem®placebo, two doses, 4 hours apart; and C=Divalproex sodium 1250 mg, oncea day at approximately 8 AM.

Results

The results below show the tests in which GHB administration wasaffected by concomitant administration of any of three MCT inhibitors,such as valproate, diclofenac, and ibuprofen.

Continuity of Attention

Xyrem® and divalproex sodium together (A+C) when compared to Xyrem®alone (A) showed a slightly delayed recovery for the combination at 4hours and 8 hours. See FIG. 5 which shows Change from Baseline Figure(LSmean with 95% CI) for Continuity of Attention (#) (PD Population).

Simple Reaction Time Mean

At 1 hour and 4 hours, Xyrem® and divalproex sodium together producedstatistically reliably greater impairments than Xyrem® alone. See FIG.6, which shows Change from Baseline Figure (LSmean with 95% CI) forSimple Reaction Time Mean (ms) (PD Population).

Digit Vigilance Accuracy

At 2.5 and 4 hours Xyrem® and divalproex sodium together werestatistically reliably different greater impairment to Xyrem® alone. SeeFIG. 7, which shows Change from Baseline Figure (LSmean with 95% CI) forDigit Vigilance Accuracy (%) (PD Population).

Tracking Distance from Target

Xyrem® and divalproex sodium together (A+C) when compared to Xyrem®alone (A) showed a statistically significant difference by a slightlydelayed recovery for the combination at 4 and 8 hours. See FIG. 8 whichshows the Change from Baseline Figure (LSmean with 95% CI) for TrackingDistance from Target (mm) (PD Population).

Numeric Working Memory Sensitivity Index

Xyrem® and divalproex sodium together (A+C) when compared to Xyrem®alone (A) showed a difference at 4.5 through 8 hours. See FIG. 9, whichshows the Change from Baseline Figure (LSmean with 95% CI) for NumericWorking Memory Sensitivity Index (#) (PD Population).

Numeric Working Memory Mean Reaction Time

Xyrem® and divalproex sodium together (A+C) when compared to Xyrem®alone (A) showed statistically significant differences at 2.5, 5 and 8hours when the combination produced greater impairment. See FIG. 10,which shows the Change from Baseline Figure (LSmean with 95% CI) forNumeric Working Memory Mean Reaction Time (ms) (PD Population).

In addition, it was observed that renal excretion of GHB increase 30%upon co-administration of Valproate.

We also found pk changes which were consistent with the inhibition ofGHB dehydrogenase. This effect will increase the exposure of GHB to thesubject and increase Cmax and AUC about 15%.

The combination of Xyrem® dosed with divalproex sodium was compared todivalproex sodium alone, more consistent statistically significantimpairments over time were seen with the combination, than when Xyrem®was compared to its placebo, indicating that the effects ofco-administration, when they appeared, were in the direction ofincreased impairments.

As has been seen previously, Xyrem® induces sleepiness and producesimpairments to attention, working memory and performance on a trackingtask in healthy volunteers. Divalproex sodium alone showed no consistentor notable effects on cognitive function or sleepiness. There wereoccasions when co-administration of Xyrem® and divalproex sodiumproduced greater deficits than Xyrem® alone. Further the combinationalso produced more consistent impairments when compared with divalproexsodium alone, than did Xyrem® when compared to its placebo. Thus thisstudy has found evidence that co-administration of Xyrem® and divalproexproduces greater impairments to cognitive function and sleepiness thanwere seen with Xyrem® alone.

Example 3

The effects of Ibuprofen were evaluated when combined with Xyrem® in amanner similar to the above. No differences were seen using the metricsabove for Karolinska Sleepiness Scale (KSS), and the following CDRSystem tasks: Simple Reaction Time, Digit Vigilance, Choice ReactionTime, Tracking and Numeric Working Memory. However, it was observed thatrenal excretion of Xyrem® doubled upon concomitant administration ofIbuprofen and Xyrem®.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing has been described insome detail by way of illustration and example for purposes of clarityof understanding, it will be readily apparent to those skilled in theart in light of the teachings of the specification that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

What is claimed is:
 1. A method for treating a patient who is sufferingfrom excessive daytime sleepiness, cataplexy, sleep paralysis, apnea,narcolepsy, sleep time disturbances, hypnagogic hallucinations, sleeparousal, insomnia, or nocturnal myoclonus with gamma-hydroxybutyrate(GHB) or a salt thereof, said method comprising: orally administering tothe patient in need of treatment an adjusted dosage amount of the GHB orsalt thereof when the patient is receiving a concomitant administrationof diclofenac.
 2. The method in accordance with claim 1, wherein theadjusted dosage amount is increased by at least about 15% of the dose ofthe GHB or salt thereof normally given to the patient.
 3. The method inaccordance with claim 1, wherein the adjusted dosage amount is increasedbetween the range of about 1% to 5%, about 5% to 10%, about 10% to 15%,about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%,about 35% to 40%, about 40% to 45%, or about 45% to 50%, relative to thedose of the GHB or salt thereof normally given to the patient.
 4. Themethod in accordance with claim 1, wherein the GHB salt is administeredat a normal dose of between 1 gram and 10 grams.
 5. The method inaccordance with claim 1, wherein the patient is suffering fromnarcolepsy.
 6. A method of safely administering GHB or a salt thereoffor excessive daytime sleepiness, cataplexy, sleep paralysis, apnea,narcolepsy, sleep time disturbances, hypnagogic hallucinations, sleeparousal, insomnia, or nocturnal myoclonus in a human patient, saidmethod comprising: determining if the patient has taken, or will take, aconcomitant dose of diclofenac; and orally administering an increasedamount of the GHB or salt thereof to the patient compared to a normaldose so as to compensate for the effects of the diclofenac on the GHB orsalt thereof when concomitantly administered.
 7. The method inaccordance with claim 6, wherein the amount of GHB or salt thereof isincreased at least 15% of the normal dose for the patient.
 8. The methodin accordance with claim 6, wherein the GHB salt is administered at anormal dose of between 1 gram and 10 grams.
 9. The method in accordancewith claim 6, herein the diclofenac is administered within two weeks ofadministration of the GHB or salt thereof.
 10. The method in accordancewith claim 6, wherein the diclofenac is administered within three daysof administration of the GHB or salt thereof.
 11. The method inaccordance with claim 6, wherein the patient is suffering fromnarcolepsy.
 12. A method for treating a patient who is suffering fromnarcolepsy, said method comprising: administering a therapeuticallyeffective amount of a formulation containing a GHB salt to a patient ata concentration of between 350 and 750 mg/ml and a pH of between 6 and10, said formulation being administered before bed and 1 to 2 hoursthereafter; determining if the patient is also being administereddiclofenac; warning of a potential drug/drug interaction due to thecombination of diclofenac and the GHB salt; and increasing the dose ofthe GHB salt at least 15% to compensate for the effect caused bydiclofenac.
 13. The method in accordance with claim 12, wherein thediclofenac is administered within two weeks of administration of the GHBsalt.
 14. The method in accordance with claim 12, wherein the diclofenacis administered within three days of administration of the GHB salt. 15.The method in accordance with claim 12, wherein the GHB salt isadministered at a concentration of between 450 to 550 mg/ml.
 16. Themethod in accordance with claim 12, wherein the GHB formulation has a pHbetween 6.5 and
 8. 17. The method in accordance with claim 12, furthercomprising administering the increased dose of the GHB salt to thepatient.
 18. The method in accordance with claim 12, wherein the GHBsalt comprises a single or a mixture of salts of GHB selected from thegroup consisting of a sodium salt of hydroxybutyrate (Na.GHB), apotassium salt of gamma-hydroxybutyrate (K.GHB), a magnesium salt ofgamma-hydroxybutyrate (Mg.(GHB)₂), and a calcium salt ofgamma-hydroxybutyrate (Ca.(GHB)₂).